Francisella tularensis is the causative agent of tularemia. Efforts to understand the pathogenesis of this particular organism are vital in that Francisella is considered to be a potential biological weapon. Its ability to cause disease and subsequently death with a relatively low inoculum has led the CDC to place Francisella on the Category A select agent list. Based on the ability of Francisella to rapidly disseminate and kill the host, particularly via the pulmonary route, we hypothesize that Francisella is capable of initially circumventing the innate immune system and that the immune response of aged mice may be altered to Francisella. To test this we have begun characterizing the immune cells and cytokines that are key players in the innate immune response in the lungs of Francisella infected mice at early time periods after infection. The virulence of the organism correlates with massive leukocyte infiltration with extensive pathology at later times post infection in various tissues depending on the route of infection. Potential key endogenous inflammatory molecules that may modulate the host responses are known as alarmins or danger associated molecular patterns (DAMPs). Studies are underway to test the role of DAMPs in the striking pathology associated with pulmonary tularemia. Finally, it is well known that aged individuals have increased morbidity and mortality due to respiratory infections. Our preliminary studies suggest that aged mice may exhibit an altered immune response to respiratory tularemia infections and perhaps may even be less capable of dealing with the pulmonary Francisella infection model. However, very little is known with regard to the potential role of DAMPs in the context of the aging immune system. We will therefore compare the innate immune response, expression of DAMPs and subsequent pathology in young adult versus aged individuals. Additionally, we will utilize ethyl pyruvate treatment, a known suppressor of inflammation, to evaluate and further dissect the role of DAMPs and pro-inflammatory mediators in young and aged mice in response to respiratory tularemia infections. The purpose of this project is to evaluate the role of damage associated molecular patterns (DAMPs) in respiratory tularemia infections. The project will also assess any alterations in the pulmonary immune response of aged mice to tularemia with an emphasis on the kinetics of cellular infiltration and the potential role of DAMPs in the alteration of the aged immune response. [unreadable] [unreadable] [unreadable]